Elsevier

Gene

Volume 527, Issue 2, 25 September 2013, Pages 565-569
Gene

The association between Interleukin (IL)-4 gene intron 3 VNTR polymorphism and alopecia areata (AA) in Turkish population

https://doi.org/10.1016/j.gene.2013.05.086Get rights and content

Highlights

  • A significant association was found between IL4 VNTR polymorphism and AA.

  • Homozygous P2P2 genotype was found to be protective against AA.

  • IL4 VNTR polymorphism may be a risk factor for the development of AA.

Abstract

Objective

Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease of hair follicles mediated by T cells. As immunological and genetic factors have been implicated in the pathogenesis of AA, the purpose of the present study was to investigate possible associations between the functional Interleukin (IL)-4 gene intron 3 VNTR polymorphism and AA susceptibility and disease progression in Turkish population.

Methods

The study group consisted of 116 unrelated patients with AA and 125 unrelated healthy controls. Genomic DNA was isolated and IL-4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers.

Results

No association was observed between AA patients and controls according to genotype distribution (p = 0.051). The allele distribution of IL-4 gene intron 3 VNTR polymorphism was statistically different between AA patients and control group (p = 0.026). The frequency of P1 allele in patients was significantly higher than that in the control group. When the P2P2 genotype was compared with P1P2 + P1P1 genotypes, a statistically significant difference was observed between patients and controls (p = 0.036). Intron 3 VNTR polymorphism in the IL-4 gene was found to be associated with AA susceptibility in Turkish population.

Conclusion

The results suggest that IL-4 VNTR polymorphism in the intron 3 region may be a risk factor for the development of AA among Turkish population. This is the first to report that intron 3 VNTR polymorphism in the IL-4 gene is associated with AA susceptibility.

Introduction

Alopecia areata (AA) is a common and genetically complex hair loss disorder that affects approximately 1–2% of the general population. AA affects both sexes and all age groups (Safavi et al., 1995). Oval patches of non-scarring hair loss which has a sudden onset and recurrent course forms are the most familiar clinical appearance of AA (Martinez-Mir et al., 2007). The exact aetiopathogenesis of AA remains unknown. However, AA is thought to be a tissue-specific autoimmune disease directed against the hair follicle causing the patient to develop antibodies to their own hair follicle structures and suppressing or stopping hair growth (Tobin, 2003). The strong association between AA and autoimmune diseases supports this idea (Garg and Messenger, 2009). AA hair follicles are surrounded by an immune infiltrate with activated T-helper cells (Th cells), cytotoxic T cells (TC cells) and natural killer (NK) cells, characterized as a Th1-type inflammatory response (Gilhar et al., 1999, Gilhar et al., 2003). Approximately 20% of affected people have a positive family history of the disease, suggesting a genetic predisposition. Hence, AA can be considered a genetically determined immune-mediated disorder (Garg and Messenger, 2009).

Interleukin-4 (IL-4) is a key cytokine secreted by Th2 lymphocytes, eosinophils and mast cells (Rocken et al., 1996) and induces the activation and differentiation of B cells and the development of the Th2 subset of lymphocytes. It has cytotoxic, anti-tumor and numerous anti-inflammatory effects (Sobti et al., 2010). The biological actions of IL-4 include stimulation of IgE and mast cell eosinophil-mediated reactions. IL-4 is the principal cytokine that stimulates B-cell immunoglobulin heavy-chain switching to the IgE isotype (Del Prete et al., 1988). It has been demonstrated that an imbalance between Th1 and Th2 cytokine production is highly correlated with the induction and development of several autoimmune diseases (Kidd, 2003).

Although there are increased levels of Th1 cytokines, Th2 immune response is also implicated in the pathogenesis of AA (Katagiri et al., 2007, Teraki et al., 1996). The role of IL-4 levels in alopecia areata patients has not been clarified yet with the controversial results taken from different studies; in some studies, it is elevated but in the others, it has decreased levels (Alzolibani et al., 2012, Attia et al., 2010, Katagiri et al., 2007, Nakamura et al., 2008; Teraki et al., 1996).

Genetic polymorphisms in cytokine genes affect gene transcription and cause inter-individual variations in cytokine production, thus influencing the outcome of infectious diseases, cancers, and autoimmune diseases (Alzolibani et al., 2012). Because of its key position in IgE production and in the induction of inflammation, IL-4 is an attractive gene thereby contributing towards autoimmunity. Polymorphisms in the IL-4 gene may change the levels of the cytokine and cause disturbance in immune functioning, and have role in several autoimmune diseases. Genetic variants of the promoter region of IL-4 have been related to elevated levels of serum IgE (Galbraith and Pandey, 1995).

There are numerous polymorphisms associated with AA. Among these, tumor necrosis factors alpha (TNFa) and beta (TNFb) have been extensively analyzed. Polymorphisms in TNFa gene have shown to be strongly associated with autoimmune/inflammatory pathologies, just like IL-4 VNTR polymorphism (Galbraith and Pandey, 1995, Schueller et al., 2006). However there is no report about the relationship of IL-4 gene intron 3 VNTR polymorphism and AA up to now. As immunological and genetic factors have been implicated in the pathogenesis of AA, the purpose of the present study was to investigate possible associations between the functional IL-4 VNTR polymorphism and AA susceptibility and disease progression in Turkish population.

Section snippets

Subjects

The study group consisted of 116 unrelated patients with AA (67 males and 49 females; mean age: 32.54 ± 9.679 standard deviation [SD] years), and 125 (63 males and 62 females; mean age: 30.06 ± 11.319 SD years) unrelated healthy controls with no scalp lesions in their personal history or on clinical examination. AA patients were gathered from Department of Dermatology of Gaziosmanpasa University, Tokat, Turkey. Clinical data were obtained from all patients, including about their demographics,

Results

The baseline clinical and demographical features of the study patients with AA were shown in Table 1. Gender, age, disease duration, number of attacks, family history, emotional stress, focal infection, nail dystrophy, alopecia severity and alopecia localization of AA patients were analyzed. Age and gender were not different between patient and control groups. The three genotypes of intron 3 VNTR polymorphism of IL-4 gene were classified as: P1P1 (183 bp–two 70 bp repeat allele), P2P2 (253 

Discussion

In this study, we investigated the association of VNTR polymorphism in the IL-4 gene with the diagnosis of AA in a group of Turkish patients to establish whether it is a risk factor or not for the development of AA. We determined statistically significant association between intron 3 VNTR polymorphism of IL-4 gene and AA susceptibility in Turkish population. To our knowledge, no previous studies have been carried out to determine the association of VNTR polymorphism in the IL-4 gene and AA in

Conclusion

In conclusion, our results strongly suggest that IL-4 gene VNTR polymorphism in the intron 3 region may be a risk factor for the development of AA among Turkish population. These results contribute to the genetic basis for AA development. Additional studies with larger populations will be necessitated in order to better illuminate the immunopathogenesis of AA.

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